Early cardiac abnormalities and increased C-reactive protein levels in a cohort of children with sleep disordered breathing

This study aims to evaluate left ventricular (LV) structure and function and inflammation in a paediatric population with sleep disordered breathing (SDB) and in control subjects. Forty-nine children with SDB and 21 healthy, age-matched subjects were enrolled. The diagnosis of obstructive sleep apnoea syndrome (OSAS) was confirmed by the laboratory polysomnography, showing an obstructive apnoea/hypopnoea index of more than one per hour, according to the criteria of the American Academy of Sleep Medicine and modified for paediatric population. Fasting blood samples for the biochemical evaluation (including high-sensitivity C-reactive protein (hsCRP) were drawn in the morning, after the polysomnographic examination in all patients with SDB and in the control group. All children underwent a two-dimensional colour Doppler cardiac examination with LV mass assessment and systolic and diastolic function evaluation. Higher hsCRP levels were observed in subjects with OSAS than in children with primary snoring and in controls (0.8 +/- 0.7 vs 0.3 +/- 0.1 ng/dl, p = 0.001, and 0.4 +/- 0.2 ng/dl, p = 0.01, respectively). The LV diastolic dysfunction was significantly more frequent in patients with severe OSAS and higher hsCRP levels than in control group. This study shows that OSAS in children is associated with higher LV mass, early LV diastolic dysfunction and a pro-inflammatory state (high CRP levels). These findings might help to explain the higher incidence of cardiovascular morbidity in patients with OSAS

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium

Sleep Power Topography in Children with Attention Deficit Hyperactivity Disorder (ADHD).

OBJECTIVE Recent years saw an increasing interest towards sleep microstructure abnormalities in attention-deficit/hyperactivity disorder (ADHD). However, the existing literature on sleep electroencephalographic (EEG) power in ADHD is still controversial, often based on single electrode recordings, and mainly focused on slow wave activity (SWA) during NREM sleep. This study aimed to systematically investigate sleep power topography in all traditional frequency bands, in all sleep stages and across sleep cycles using high-density EEG (HD-EEG). METHOD Thirty drug-naïve children with ADHD (10.5 ± 2.1 years, 21 male) and 23 typically developing (TD) control participants (mean age: 10.2 ± 1.6 years, 13 male) were included in the current analysis. Signal power topography was computed in classical frequency bands during sleep, contrasted between groups and sleep cycles, and correlated with measures of ADHD severity, cognitive functioning and estimated total sleep time. RESULTS Compared to TD subjects, patients with ADHD consistently displayed a widespread increase in low-frequency activity (between 3 and 10 Hz) during NREM sleep, but not during REM sleep and wake before sleep onset. Such a difference involved a wide centro-posterior cluster of channels in the upper SWA range, in Theta, and low-Alpha. Between-group difference was maximal in sleep stage N3 in the first sleep cycle, and positively correlated with average total sleep time. CONCLUSIONS These results support the concept that children with ADHD, compared to TD peers, have a higher sleep pressure and altered sleep homeostasis, which possibly interfere with (and delay) cortical maturation

Sleep clinical record: an aid to rapid and accurate diagnosis of paediatric sleep disordered breathing

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Acquisition Parameters Influence Diffusion Metrics Effectiveness in Probing Prostate Tumor and Age-Related Microstructure

: This study aimed to investigate the Diffusion-Tensor-Imaging (DTI) potential in the detection of microstructural changes in prostate cancer (PCa) in relation to the diffusion weight (b-value) and the associated diffusion length lD. Thirty-two patients (age range = 50-87 years) with biopsy-proven PCa underwent Diffusion-Weighted-Imaging (DWI) at 3T, using single non-zero b-value or groups of b-values up to b = 2500 s/mm2. The DTI maps (mean-diffusivity, MD; fractional-anisotropy, FA; axial and radial diffusivity, D// and D┴), visual quality, and the association between DTI-metrics and Gleason Score (GS) and DTI-metrics and age were discussed in relation to diffusion compartments probed by water molecules at different b-values. DTI-metrics differentiated benign from PCa tissue (p ≤ 0.0005), with the best discriminative power versus GS at b-values ≥ 1500 s/mm2, and for b-values range 0-2000 s/mm2, when the lD is comparable to the size of the epithelial compartment. The strongest linear correlations between MD, D//, D┴, and GS were found at b = 2000 s/mm2 and for the range 0-2000 s/mm2. A positive correlation between DTI parameters and age was found in benign tissue. In conclusion, the use of the b-value range 0-2000 s/mm2 and b-value = 2000 s/mm2 improves the contrast and discriminative power of DTI with respect to PCa. The sensitivity of DTI parameters to age-related microstructural changes is worth consideration

A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells

Tab2, originally described as a component of the inflammatory pathway, has been implicated in phenomena of gene de-repression in several contexts, due to its ability to interact with the NCoR corepressor. Tab2 interacts also with steroid receptors and dismisses NCoR from antagonist-bound Estrogen and Androgen Receptors on gene regulatory regions, thus modifying their transcriptional activity and leading to pharmacological resistance in breast and prostate cancer cells. We demonstrated previously that either Tab2 knock-down, or a peptide mimicking the Estrogen Receptor alpha domain interacting with Tab2, restore the antiproliferative response to Tamoxifen in Tamoxifen-resistant breast cancer cells. In this work, we map the domain of Tab2 responsible of Estrogen Receptor alpha interaction. First, using both co-immunoprecipitation and pull-down with recombinant proteins, we found that the central part of Tab2 is primarily responsible for this interaction, and that this region also interacts with Androgen Receptor. Then, we narrowed down the essential interaction region by means of competition assays using recombinant protein pull-down. The interaction motif was finally identified as a small region adjacent to, but not overlapping, the Tab2 MEKK1 phosphorylation sites. A synthetic peptide mimicking this motif efficiently displaced Tab2 from interacting with recombinant Estrogen Receptor alpha in vitro, prompting us to test its efficacy using derivatives of the MCF7 breast carcinoma cell lines that are spontaneously resistant to Tamoxifen. Indeed, we observed that this mimic peptide, made cell-permeable by addition of the TAT minimal carrier domain, reduced the growth of Tamoxifen-resistant MCF7 cells in the presence of Tamoxifen. These data indicate a novel functional domain of the Tab2 protein with potential application in drug design

Electrophysiological and Neuropsychological Indices of Cognitive Dysfunction in Patients with Chronic Insomnia and Severe Benzodiazepine Use Disorder.

Benzodiazepine (BDZ) misuse is a growing health problem, with 1-2% of patients under BDZ treatment meeting the criteria for use disorder or dependence. Although BDZ addiction potential has been known for decades, much remains unknown its effects on brain functions. The aim of this study was to assess the neuropsychological and neurophysiological profile of a group of chronic insomniacs taking long-term high doses of benzodiazepine. We recruited 17 consecutive patients admitted to our third-level Sleep Medicine Unit for drug discontinuation (7 males, mean age 49.2 ± 11.2 years, mean education 13.7 ± 3.9 years, mean daily diazepam-equivalent BDZ: 238.1 ± 84.5 mg) and 17 gender/age-matched healthy controls (7 males, mean age 46.8 ± 14.1 years, mean education 13.5 ± 4.5 years). We performed a full neuropsychological evaluation of all subjects and recorded their scalp event-related potentials (Mismatch-Passive Oddball-Paradigm and Active Oddball P300 Paradigm). Patients with chronic insomnia and BDZ use disorder showed a profound frontal lobe executive dysfunction with significant impairment in the cognitive flexibility domain, in face of a preserved working, short and long-term memory. In patients, P300 amplitude tended to be smaller, mainly over the frontal regions, compared to controls. BDZ use disorder has a severe cognitive impact on chronic insomnia patients. Long-term high-dose BDZ intake should be carefully evaluated and managed by clinicians in this specific patient population, especially in relation to risky activities

Association between Thymic Function and Allogeneic Hematopoietic Stem Cell Transplantation Outcome: Results of a Pediatric Study

Abstract Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities